Christoph Stellbrink

Effect of Pacing Chamber and Atrioventricular Delay on Acute Systolic Function of Paced Patients With Congestive Heart Failure

BACKGROUND Previous studies of pacing therapy for dilated congestive heart failure (CHF) have not established the relative importance of pacing site, AV delay, and patient heterogeneity on outcome. These variables were compared by a novel technique that evaluated immediate changes in hemodynamic function during brief periods of atrial-synchronous ventricular pacing. METHODS AND RESULTS Twenty-seven CHF patients with severe left ventricular (LV) systolic dysfunction and LV conduction disorder were implanted with endocardial pacing leads in the right atrium and right ventricle (RV) and an epicardial lead on the LV and instrumented with micromanometer catheters in the LV, aorta, and RV. Patients in normal sinus rhythm were stimulated in the RV, LV, or both ventricles simultaneously (BV) at preselected AV delays in a repeating 5-paced/15-nonpaced beat sequence. Maximum LV pressure derivative (LV+dP/dt) and aortic pulse pressure (PP) changed immediately at pacing onset, increasing at a patient-specific optimal AV delay in 20 patients with wide surface QRS (180+/-22 ms) and decreasing at short AV delays in 5 patients with narrower QRS (128+/-12 ms) (P<0.0001). Overall, BV and LV pacing increased LV+dP/dt and PP more than RV pacing (P<0.01), whereas LV pacing increased LV+dP/dt more than BV pacing (P<0.01). CONCLUSIONS In this population, CHF patients with sufficiently wide surface QRS benefit from atrial-synchronous ventricular pacing, LV stimulation is required for maximum acute benefit, and the maximum benefit at any site occurs with a patient-specific AV delay.

long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay

OBJECTIVES We sought to compare the short- and long-term clinical effects of atrial synchronous pre-excitation of one (univentricular) or both ventricles (biventricular), that provide cardiac resynchronization therapy (CRT). BACKGROUND In patients with heart failure (HF) who have a ventricular conduction delay, CRT improves systolic hemodynamic function. The clinical benefit of CRT is still being investigated. METHODS Forty-one patients were randomized to four weeks of first treatment with biventricular or univentricular stimulation, followed by four weeks without treatment, and then four weeks of a second treatment with the opposite stimulation. The best CRT stimulation was continued for nine months. Cardiac resynchronization therapy was optimized by hemodynamic testing at implantation. The primary end points were exercise capacity measures. Data were analyzed by two-way repeated-measures analysis of variance. RESULTS The left ventricle was selected for univentricular pacing in 36 patients. The clinical effects of univentricular and biventricular CRT were not significantly different. The results of each method were pooled to assess sequential treatment effects. Oxygen uptake during bicycle exercise increased from 9.48 to 10.4 ml/kg/min at the anaerobic threshold (p = 0.03) and from 12.5 to 14.3 ml/kg/min at peak exercise (p < 0.001) with the first treatment, and from 10.0 to 10.7 ml/kg/min at the anaerobic threshold (p = 0.2) and from 13.4 to 15.2 ml/kg/min at peak exercise (p = 0.002) with the second treatment. The 6-min walk distance increased from 342 m at baseline to 386 m after the first treatment (p < 0.001) and to 416 m after the second treatment (p = 0.03). All improvements persisted after 12 months of therapy. CONCLUSIONS Cardiac resynchronization therapy produces a long-term improvement in the clinical symptoms of patients with HF who have a ventricular conduction delay. The differences between optimized biventricular and univentricular therapy appear to be small for short-term treatment.

The Pacing Therapies for Congestive Heart Failure (PATH-CHF) Study: Rationale, Design, and Endpoints of a Prospective Randomized Multicenter Study

In conjunction with pharmacologic therapy, pacing has been proposed as a potential treatment to decrease symptoms in patients with moderate-to-severe congestive heart failure (CHF). Uncontrolled studies of pacing therapy for CHF dealing with different pacing sites, modes of pacing, and atrioventricular delays have reported mixed outcomes. The Pacing Therapies in Congestive Heart Failure (PATH-CHF) study is a single-blind, randomized, crossover, controlled trial designed to evaluate the effects of pacing on acute hemodynamic function and to assess chronic clinical benefit in patients with moderate-to-severe CHF. The effect of pacing on oxygen consumption at peak exercise and at anaerobic threshold during cardiopulmonary exercise tests, and on 6-minute walk distance, have been selected as primary endpoints of the study. Secondary endpoints of the trial were changes in New York Heart Association (NYHA) functional class, quality-of-life as assessed by the Minnesota Living with Heart Failure questionnaire, and hospitalization frequency. Finally, changes in ejection fraction, cardiac output, and filling pattern were assessed by echocardiography. The trial was planned to include 53 patients from 7 centers in Europe over a period of 3 years. The study was divided into 2 parts: acute testing and chronic follow-up. The acute study, performed during the pacemaker implantation, involved extensive testing using a custom-designed computer (FLEXSTIM) and a unique burst pacing protocol (FLEXSTIM protocol) to determine the best ventricular pacing sites and the most appropriate atrioventricular delays. The chronic phase consisted of a crossover study designed to test in each patient the best univentricular pacing site and biventricular pacing as assessed by the acute hemodynamic study. The study started with the first implant in 1995 and has, to date, included 42 patients. The study is expected to be completed by the end of 1998. The results of a first interim analysis showed trends toward improvement in all primary and secondary endpoints during the pacing periods compared with no pacing.

Echocardiographic quantification of left ventricular asynchrony predicts an acute hemodynamic benefit of cardiac resynchronization therapy

OBJECTIVES We sought to determine whether radial left ventricular (LV) asynchrony in patients with heart failure predicts systolic function improvement with cardiac resynchronization therapy (CRT). BACKGROUND We quantified LV wall motion by echocardiography to correlate the effects of CRT on LV systolic function with wall motion synchrony. METHODS Thirty-four patients underwent echocardiographic phase analysis of LV septal and lateral wall motion and hemodynamic testing before CRT. Phase relationships were measured by the difference between the lateral (Phi(L)) and septal (Phi(S)) wall motion phase angles: Phi(LS) = Phi(L) - Phi(S). The absolute value of Phi(LS) was used as an order-independent measure of synchrony: the absolute value Phi(LS) = the absolute value of Phi(L) - Phi(S). RESULTS Three phase relationships were identified (mean +/- SD): type 1 (n = 4; peak positive LV pressure [dP/dt(max)] 692 +/- 310 mm Hg/s; Phi(LS) = 5 +/- 6 degrees, synchronous wall motion); type 2 (n = 17; dP/dt(max) 532 +/- 148 mm Hg/s; Phi(LS) = 77 +/- 33 degrees, delayed lateral wall motion); and type 3 (n = 13; dP/dt(max) 558 +/- 154 mm Hg/s; Phi(LS) = -115 +/- 33 degrees, delayed septal wall motion, triphasic). A large absolute value of Phi(LS) predicted a larger increase in dP/dt(max) with CRT (r = 0.74, p < 0.001). Sixteen patients were studied during right ventricular (RV), LV and biventricular (BV) pacing. Cardiac resynchronization therapy acutely reduced the absolute value of Phi(LS) from 104 +/- 41 degrees (OFF) to 86 +/- 45 degrees (RV; p = 0.14 vs. OFF), 71 +/- 50 degrees (LV; p = 0.001 vs. OFF) and 66 +/- 42 degrees (BV; p = 0.001 vs. OFF). A reduction in the absolute value of Phi(LS) predicted an improvement in dP/dt(max) in type 2 patients for LV (r = 0.87, p = 0.005) and BV CRT (r = 0.73, p = 0.04). CONCLUSIONS Echocardiographic quantification of LV asynchrony identifies patients likely to have improved systolic function with CRT. Improved synchrony is directly related to improved hemodynamic systolic function in type 2 patients.

Cardiac resynchronization therapy can reverse abnormal myocardial strain distribution in patients with heart failure and left bundle branch block.

OBJECTIVES We studied the effects of cardiac resynchronization therapy (CRT) on regional myocardial strain distribution, as determined by echocardiographic strain rate (SR) imaging. BACKGROUND Dilated hearts with left bundle branch block (LBBB) have an abnormal redistribution of myocardial fiber strain. The effects of CRT on such abnormal strain patterns are unknown. METHODS We studied 18 patients (12 males and 6 females; mean age 65 +/- 11 years [range 33 to 76 years]) with symptomatic systolic heart failure and LBBB. Doppler myocardial imaging studies were performed to acquire regional longitudinal systolic velocity (cm/s), systolic SR (s(-1)), and systolic strain (%) data from the basal and mid-segments of the septum and lateral wall before and after CRT. By convention, negative SR and strain values indicate longitudinal shortening. RESULTS Before CRT, mid-septal peak SR and peak strain were lower than in the mid-lateral wall (peak SR: -0.79 +/- 0.5 [septum] vs. -1.35 +/- 0.8 [lateral wall], p < 0.05; peak strain: -7 +/- 5 [septum] vs. -11 +/- 5 [lateral wall], p < 0.05). This relationship was reversed during CRT (peak SR: -1.35 +/- 0.8 [septum] vs. -0.93 +/- 0.6 [lateral wall], p < 0.05; peak strain: -11 +/- 6 [septum] vs. -7 +/- 6 [lateral wall], p < 0.05). Cardiac resynchronization therapy reversed the septal-lateral difference in mid-segmental peak strain from -46 +/- 94 ms (LBBB) to 17 +/- 92 ms (CRT; p < 0.05). CONCLUSIONS Left bundle branch block can lead to a significant redistribution of abnormal myocardial fiber strains. These abnormal changes in the extent and timing of septal-lateral strain relationships can be reversed by CRT. The noninvasive identification of specific abnormal but reversible strain patterns should help to improve patient selection for CRT.

Transvenous biventricular pacing for heart failure: can the obstacles be overcome?☆

Despite increasing evidence of hemodynamic benefit and long-term improvement in clinical status of congestive heart failure (CHF) patients with left ventricular and biventricular pacing, the risks and technical limitations of placing a permanent left ventricular pacing lead have prevented widespread clinical adoption of this therapy. Results of this and other recent investigations suggest it is necessary to target specific sites on the left ventricle to maximize hemodynamic benefit. However, limitations and variations of coronary vein anatomy, as well as patient safety, lead dislodgement, pacing thresholds, lead handling, and ease-of-use issues, present technical challenges for current transvenous permanent pacing lead designs. However, a new transvenous lead system based on an over-the-wire design appears to solve many of these problems and has proved feasible in acute clinical studies.

Safety and Efficacy of Enoxaparin Compared With Unfractionated Heparin and Oral Anticoagulants for Prevention of Thromboembolic Complications in Cardioversion of Nonvalvular Atrial Fibrillation The Anticoagulation in Cardioversion using Enoxaparin (ACE) Trial

Background—Anticoagulation in cardioversion of atrial fibrillation is currently performed with unfractionated heparin (UFH) and oral anticoagulants, with or without guidance by transesophageal echocardiography (TEE). Low-molecular-weight heparins may reduce the risk of bleeding, may obviate the need for intravenous access, and do not require frequent anticoagulation monitoring. Methods and Results—In a randomized, prospective multicenter trial, we compared the safety and efficacy of enoxaparin administered subcutaneously with intravenous UFH followed by the oral anticoagulant phenprocoumon in 496 patients scheduled for cardioversion of atrial fibrillation of >48 hours’ and ≤1 year’s duration. Patients were stratified to cardioversion with (n=431) and without (n=65) guidance by TEE. The study aimed to demonstrate noninferiority of enoxaparin compared with UFH+phenprocoumon with regard to the incidence of embolic events, all-cause death, and major bleeding complications. Secondary end points included successful cardioversion, maintenance of sinus rhythm until study end, and minor bleeding complications. Of 496 randomized patients, 428 were analyzed per protocol. Enoxaparin was noninferior to UFH+phenprocoumon with regard to the incidence of the composite primary end point in a per-protocol analysis (7 of 216 patients versus 12 of 212 patients, respectively; P =0.016) and in an intention-to-treat analysis (7 of 248 patients versus 12 of 248 patients, respectively; P =0.013). There was no significant difference between the 2 groups in the number of patients reverted to sinus rhythm. Conclusions—Enoxaparin is noninferior to UFH+phenprocoumon for prevention of ischemic and embolic events, bleeding complications, and death in TEE-guided cardioversion of atrial fibrillation. Its easier application and more stable anticoagulation may make it the preferred drug for initiation of anticoagulation in this setting.

Cardiac resynchronization therapyhomogenizes myocardial glucosemetabolism and perfusion in dilatedcardiomyopathy and left bundle branch block

Abstract Objectives We investigated whether cardiac resynchronization therapy (CRT) affects myocardial glucose metabolism and perfusion in dilated cardiomyopathy (DCM) and left bundle branch block (LBBB). Background Patients with DCM and LBBB present with asynchronous left ventricular (LV) activation, leading to reduced septal glucose metabolism. Cardiac resynchronization therapy recoordinates LV activation, but its effects on myocardial glucose metabolism and perfusion remain unknown. Methods In 15 patients (10 females; 61 ± 13 years) with DCM and LBBB (QRS width 165 ± 15 ms), gated 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and technetium-99m ( 99m Tc)-sestamibi single-photon emission computed tomography were performed before and after two weeks of CRT. Uptake of FDG and 99m Tc-sestamibi was determined in four LV wall areas. Ejection fraction and volumes were calculated from gated PET. Results Baseline FDG uptake was heterogeneous (p 99m Tc-sestamibi uptake was modest (lowest septal 65 ± 10%; maximum lateral 84 ± 5%) and also reduced with CRT, although some heterogeneity (p 99m Tc-sestamibi uptake (0.77 ± 0.13 to 0.85 ± 0.16, p Conclusions Glucose metabolism is reduced more than perfusion in the septal compared with LV lateral wall in patients with DCM and LBBB. Cardiac resynchronization therapy restores homogeneous myocardial glucose metabolism with less influence on perfusion.

Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort

OBJECTIVE Although AF-induced atrial contractile dysfunction has significant clinical implications the underlying intracellular mechanisms are poorly understood. METHODS From the right atrial appendages of 59 consecutive patients undergoing mitral valve surgery (31 in SR, 28 in chronic AF) thin muscle preparations (diameter<0.7 mm) were isolated. Isometric force of contraction was measured in the presence of different concentrations of Ca(2+) and isoprenaline. To assess the function of the sarcoplasmic reticulum, the force-frequency relationship and the post-rest potentiation were studied. The myocardial density of the ryanodine-sensitive calcium release channel (CRC) of the sarcoplasmic reticulum was determined by [3H]ryanodine binding. Myocardial content of SR-Ca(2+)-ATPase (SERCA), phospholamban (Plb), calsequestrin (Cals) and the Na(+)/Ca(2+)-exchanger (NCX) were analyzed by Western blot analysis. Adenylyl cyclase activity was measured with a radiolabeled bioassay using [32P]ATP as a tracer. RESULTS In 72 muscle preparations of SR patients contractile force was 10.9+/-1.8 mN/mm(2) compared to 3.3+/-0.9 mN/mm(2) (n=48, P<0.01) in AF patients. The positive inotropic effect of isoprenaline was diminished but the stimulatory effect on relaxation and the adenylyl cyclase were not altered in AF patients. The force-frequency relation and the post-rest potentiation were enhanced in atrial myocardium of AF patients. The protein levels of CRC, SERCA, Plb, and Cals were not different between the two groups. In contrast, the Na(+)/Ca(2+)-exchanger was upregulated by 67% in atria of AF patients. CONCLUSIONS AF-induced atrial contractile dysfunction is not due to beta-adrenergic desensitization or dysfunction of the sarcoplasmic reticulum and thus is based on different cellular mechanisms than a ventricular tachycardia-induced cardiomyopathy. Instead, downregulation or altered function of the L-type Ca(2+)-channel and an increased Ca(2+) extrusion via the Na(+)/Ca(2+)-exchanger seem to be responsible for the depressed contractility in remodeled atria.

Potential benefit of biventricular pacing in patients with congestive heart failure and ventricular tachyarrhythmia.

Treatment of congestive heart failure (CHF) aims for symptomatic relief and reduction of mortality both from sudden death and pump failure. The implantable cardioverter defibrillator (ICD) is highly effective in the prevention of sudden death, but no mortality benefit in advanced CHF has yet been shown. Biventricular pacing may lead to functional improvement in selected patients with CHF. Thus, a biventricular pacemaker with defibrillation capabilities may be ideal for patients with advanced CHF. We retrospectively analyzed the data from 384 patients (age 59 +/- 12 years, 322 male and 62 female) with regard to New York Heart Association (NYHA) CHF class, mean QRS duration, mean PR interval, presence of a QRS > 120 msec and incidence of atrial fibrillation at the time of ICD implantation. Based on eligibility criteria from studies in biventricular pacing, we analyzed how many patients may benefit from biventricular pacing. Patients with CHF were older (NYHA class III: 60.9 +/- 9.7, class II: 61.3 +/- 10 versus class I: 50.8 +/- 13.6 years, p < 0.001 each) and mean QRS duration was longer with advanced CHF (NYHA class III 127.8 +/- 30 msec; class II 119.4 +/- 27.7 msec; class 0-1: 103.9 +/- 17.7 msec, p < 0.001, analysis of variance) as was the mean PR interval (NYHA class III 189.9 +/- 33.5 msec; class II 176.1 +/- 29.3 msec; class 0-1 162.7 +/- 45.9 msec, p < 0.001, analysis of variance). The incidence of atrial fibrillation was higher in class III (25.5%) compared with class 0-1 (16.9%) and class II patients (14.1%, p = 0.043, chi-square test). A total of 28 patients (7.3%) fulfilled eligibility criteria for biventricular pacing if NYHA class III patients were considered candidates and 48 (12.5%) if patients with NYHA II CHF and ejection fraction < or = 30% were included. Thus, biventricular pacing may offer a promising therapeutic approach for a significant proportion of patients with CHF at risk for ventricular tachyarrhythmia.